TIME TO BENEFIT in Atorvastatin Trials

TAKE HOME MESSAGES

FACTS

TIME TO BENEFIT in Atorvastatin Trials

Number of patient with CV disease will increase in upcoming years As one of the main risk factors, dyslipidemia can be modified As Physician, we can DO MORE to our patients

TIME TO BENEFIT in Atorvastatin Trials

How you DO MORE to your patient:

1. 2. 3. 4. Access patients CV Risk Achieve target goals according NCEP ATP III CV risk of your patients as soon as possible Educate your patient

ATORVASTATIN CLINICAL OUTCOME TRIAL

ASCOT-LLA
Hypertensive patient with 2> risk factors

TIME TO BENEFIT in Atorvastatin Trials

CARDS
DM type II patient w/ 1> risk factors

SPARCL
Stroke PAtient

PROVE-IT
ACS patient w/ hyperlipidemia

NonFatal MI & Fatal CHD

Major CV Events

Fatal & non Fatal Stroke

Composite primary endpoint

36 %
RRR

37%
RRR

16 %
RR R

16 %
RR R

ATORVASTATIN SHOWS EARLY CLINICAL BENEFIT IN BROAD RANGE OF PATIENT FOR PRIMARY AND SECONDARY PREVENTION

ASCOT-LLA Primary End Point: Nonfatal MI and Fatal CHD

The Event Curves Separate as Early as 90 Days and Diverge Over Time
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TIME TO BENEFIT in Atorvastatin Trials

Cumulative Incidence (%)

# of Events 100 154

End of Treatment Mean LDL 90 mg/dL 126 mg/dL

36%
Relative Risk Reduction (P=0.0005) HR=0.64 (0.500.83) Placebo Atorvastatin 10 mg

Atorvastatin 10 mg Placebo

5,168 5,137

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.3

5.0

Years
In a post-hoc analysis, a significant difference at 90 days was observed between treatment groups HR = hazard ratio Due to a significant reduction in the primary end point, the trial was stopped after only 3.3 years, nearly 2 years earlier than expected

Adapted from Sever PS, et al. Lancet. 2003;361:1149-1158.

ASCOT-LLA Post Hoc Time-to-Benefit Analysis: Cardiac Events

Risk Reduction (%) 83 67 48 45 38 36 0 0.5 1.0 1.5 2.0

TIME TO BENEFIT in Atorvastatin Trials

Event Rate* Censoring Time 30 days 90 days 180 days 1 year 2 years End of study Hazard Ratio (95% CI) Atorvastatin 2.4 5.5 7.5 6.6 5.9 6.0 Placebo 14.2 16.6 14.3 12.0 9.5 9.4

Atorvastatin Better

Placebo Better

* Per 1000 patient-years. CI = confidence interval. Reproduced from Sever PS et al. Am J Cardiol. 2005;96(suppl):39F-44F, with permission.

CARDS: Primary End Point Major CV Events* Acute Coronary Heart Disease Events, Coronary Revascularization, or Stroke
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n

TIME TO BENEFIT in Atorvastatin Trials

Cumulative Hazard (%)

# of Events 83
127

End of Treatment Median LDL

Placebo Atorvastatin 10 mg

Atorva 10 mg

1,428
1,410

77 mg/dL
120 mg/dL

10

Placebo

37%
Relative Risk Reduction

(P=0.001)
5

(95% CI: 1752)

0 0.0 1.0 2.0 3.0 3.9 4.75

% Years
Trial Stopped Early
The study was stopped 2 years earlier than anticipated after a median follow up of 3.9 years, due to beneficial effect of atorvastatin The results were similar in patients with LDL-C <120 mg/dL (3.1 mmol/L) and 120 mg/dL (3.1 mmol/L)
1. Adapted from Colhoun HM, et al. Lancet. 2004;364:685-696. 2. Data on File, Pfizer Inc.

CARDS Post Hoc Time-to-Benefit Analysis: Major Cardiovascular Events

2

TIME TO BENEFIT in Atorvastatin Trials

1.5 Hazard Ratio (95% CI)

HR = 0.63 0.5
(95% CI = 0.48-0.83)

0 1 2 3 4 4.5

Time (years)

Adapted from Colhoun HM et al. Diabetologia. 2005;48:2482-2485, with permission.

TIME TO BENEFIT in Atorvastatin Trials

Lipitor can to give the POWER TO DO MORE for your patients

Lipitor Shows Established Data in Vasculoprotective effect: Ox-LDL Hs-CRP Plaque Regression and Stabilization
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TIME TO BENEFIT in Atorvastatin Trials

Achieving LDL-C is Important But

Having a rapid clinical benefit is also IMPORTANT

Because Were treating human being, not laboratory figures
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Conclusions

TIME TO BENEFIT in Atorvastatin Trials

Achieving LDL-C target is Important, BUT having rapid and fast clinical benefits is also IMPORTANT Atorvastatin has been shown Target goals achievement in several studies The early time to CV benefit is shown in several Atorvastatin trials: PROVE IT -CARDS REVERSAL -ASCOT-LLA Early benefits may be related more to LDL-independent (pleiotropic) effects of statins, whereas both lipid-dependent and -independent effects may be responsible for longer-term benefits

Distinct molecular structures may account for differences in pleiotropic effects

these benefits extend beyond any dose-dependent lipid-lowering effects
Sever PS et al. Lancet. 2003;361:1149-1158; Colhoun HM et al. Lancet. 2004;364:685-696; Schwartz GG et al. JAMA. 2001;285:1711-1718; Cannon CP et al. N Engl J Med. 2004;350:1495-1504; Koren MJ, Hunninghake DB. J Am Coll Cardiol. 2004;44:1772-1779; Nissen SE et al. JAMA. 2004;291:1071-1080; Smilde TJ et al. Lancet. 2001;357:577-581; Cannon CP et al. Circulation. 2004;110(suppl III);III-499; Marchesi S et al. J Cardiovasc Pharmacol. 2000;36:617-621; Ridker PM et al. N Engl J Med. 2005;532:20-28; Walter MF et al. J Am Coll Cardiol. 2004;43(5 pt A):529A; Gupta S. Int J Cardiol. 2004;96:131-139.

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Conclusions
Accumulating evidence suggests that atorvastatin may have vasculoprotective effects beyond lipid lowering, including:

TIME TO BENEFIT in Atorvastatin Trials

Inhibit process of Ox-LDL Reducing CRP and other markers of inflammation Increasing plaque stability by reducing plaque volume and oxidative stress

Long-term reduction in clinical events and atherosclerosis progression is related to reduction in both inflammation and lipids (dual goals)

Sever PS et al. Lancet. 2003;361:1149-1158; Colhoun HM et al. Lancet. 2004;364:685-696; Schwartz GG et al. JAMA. 2001;285:1711-1718; Cannon CP et al. N Engl J Med. 2004;350:1495-1504; Koren MJ, Hunninghake DB. J Am Coll Cardiol. 2004;44:1772-1779; Nissen SE et al. JAMA. 2004;291:1071-1080; Smilde TJ et al. Lancet. 2001;357:577-581; Cannon CP et al. Circulation. 2004;110(suppl III);III-499; Marchesi S et al. J Cardiovasc Pharmacol. 2000;36:617-621; Ridker PM et al. N Engl J Med. 2005;532:20-28; Walter MF et al. J Am Coll Cardiol. 2004;43(5 pt A):529A; Gupta S. Int J Cardiol. 2004;96:131-139.

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TIME TO BENEFIT in Atorvastatin Trials

TREATMENT GOAL: We have to prevent CV morbidity and mortality as soon as possible..!!

TIME TO BENEFIT in Atorvastatin Trials

THANK YOU

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